The ST5 gene has been identified as a candidate tumor suppressor gene located on chromosome 11. The gene product has three isoforms: 126, 82 and 70 kD in size, respectively, translated from 4.6, 3.1 and 2.8 kb transcripts. This protein has structural features which suggest involvement in cell signaling pathways. Initial work associated expression of the tumorigenic phenotype in HeLa/fibroblast hybrid cell lines with the absence of the 2.8 kb transcript. Subsequently, p126 was found to stimulate MAP kinase activity. This activity is blocked by p70. These findings correlate well with the earlier morphological findings, suggesting a role for p126 in the expression of the transformed phenotype. Presently, the challenge is to elucidate the role p126 plays in cell signal pathways by first identifying proteins with which it interacts in vivo. The rationale here is that pl26. as part of a cell signaling pathway, will interact with other proteins also identified as being part of cell signaling pathways. The next steps will be to characterize the nature of the interaction between these proteins and p126 and to determine the intracellular consequences of this interaction with respect to MAP kinase activity. These experiments should provide a greater understanding of the role of p126 in cell signaling pathways.